Patent CA-2035385-A1 (CA)
Title: Glycosyl prodrugs of anthracyclines, a process for the preparation thereof and the use thereof in combination with unctionalized tumor -specific enzyme conjugates
Inventor: GERKEN MANFRED
IPC: A61K31/7034
Filed: 1991-01-31
Abstract: Abstract of the disclosure:            Glycosyl prodrugs of anthracyclines, a process for the preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates The invention relates to glycosyl prodrugs of anthra-cyclines, a process for the preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugtes for treating cancers, and it specifically relates to 14-O-glycosylanthracyclines as prodrugs which can be cleaved by the action of tumor-specific enzyme conjugates to cytotoxic active substan-ces, where the liberated active substance is suitable because of its cytotoxic activity for the treatment of cancers.            The invention relates to 14-O-glycosylanthracyclines of the formula I and the salts thereof with an inorganic or organic acid         I   in which R1, R2 and R3 are, independently of one another, hydrogen, hydroxyl, methoxy, R4, R5 and R6 are, independently of one another, hydrogen, hydroxyl,   halogen,   aliphatic  acyloxy   (C1-C8), benzoyloxy or substituted benzoyloxy such as para-nitrobenzoyloxy,    alkyloxy   (C1-C8),    allyloxy, benzyloxy  or  substituted  benzyloxy, tetrahydro-pyranyloxy, amino, NH-acyl (C1-C8), NH-(9-fluorenyl-methoxycarbonyl),    morpholino    or    substituted morpholino,  preferably 3-O-methylmorpholino or 2-cyanomorpholino, R7 is a carbohydrate of the formula II                     II     with R8  being methyl, hydroxymethyl, acyloxymethyl (C1-C8), alkyloxymethyl  (C1-C8), benzyloxymethyl,  allyloxy-methyl, carboxyl, carboxymethyl or carboxyallyl, R9, R10 and R11 are, independently of one another, hydro-gen, hydroxyl, acyloxy (C1-C8), benzoyloxy or substi-tuted  benzoyloxy  such  as  para-nitrobenzoyloxy, alkyloxy (C1-C8), allyloxy, benzyloxy or substituted benzyloxy,   amino,   NH-acyl   (C1-C8)   or  NH-(9-fluorenylmethoxycarbonyl).            Compounds in which R4=R5=R9=R10=O-acetyl and R5-R11=H in the alpha-L-deoxyfucose conformation are excepted.            A functionalized tumor-specific enzyme is intended to mean within the scope of the invention an enzyme of the formula III                          A-Sp-E III in which A    is an antibody or one of its fragments which have specificity for a tumor-associatad antigen, or a biomolecule which accumulates in a tumor, such as EGF (epidermal growth factor), TGF-.alpha. (transforming growth  factor .alpha.),  PDGF  (platelet-derived growth factor), IGF I+II (insulin-like growth factor I+II) or a+b FGF (acidic + basic fibroblast growth factor) E    is a glycosidase of little or no immunogenicity, preferably a mammalian glycosidase such as .alpha.- or .beta.-glucosidase, .alpha.-galactosidase, .alpha.- or .beta.-mannosidase, .alpha.-fucosidase,   N-acetyl-.alpha.-galactosaminidase,   .beta.-acetyl-.beta.-/N-acetyl-.alpha.-glucosaminidase or .beta.-glucuroni-dase, and Sp  (spacer)  is  a bifunctional  sulfide or disulfide-containing group of the formula IV        X(S)nY    IV        or        (S)n in which X or Y is -CO-R12(N-succinimido)- or -C(=R13)-CH2-CH2- with R12 being -CH2-CH2-, 1,4-cyclohexylidene, 1,3- or 1,4-phenylene or methoxycarbonyl- or chloro-1,4-phenyl-ene and R14 is O or NH, Y    is -C(=R13)-CH2-CH2- where R13 has the stated meaning, and n   is 1 or 2, or a polypeptide spacer.